TDP-43 (TAR DNA-Binding Protein 43) was identified as a protein that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs and represses transcription of viral RNA (Ou, S., J Virol., 69(6):3584-96, 1995). TDP-43 was also identified as a splicing regulator that binds to the (UG)m-repeated polymorphic region near the 3′ splice site of CFTR exon 9 and down-regulates its recognition by the splicing machinery (Buratti, E. and Baralle F E, J Biol Chem., 276(39):36337-43, 2001 and references therein). Notably, exon 9 skipping produces a nonfunctional CFTR protein and is associated with some forms of cystic fibrosis. It was also observed that TDP-43 recognizes (UG) repeats in other contexts.
Hyperphosphorylated, ubiquitinated, C-terminal fragments of TDP-43 have been recovered from the central nervous system (e.g., hippocampus, neocortex, and spinal cord) from patients with frontotemporal lobar degeneration (FTLD) with ubiquitin-positive inclusions and amyotrophic lateral sclerosis (ALS) and is believed to be the hallmark pathological feature of FTLD and ALS (Neumann et al. Science, 314(5796):130-3. 2006). The presence or amount of abnormal aggregation of phosphorylated and ubiquitinated TDP-43 is believed to define a novel class of neurodegenerative diseases referred to as “TDP-43 proteinopathies” (Cairns et al. (2007) The American Journal of Pathology 171(1):227).